9-128222544-G-C

Variant names:

• chr9-128222544-G-C
• rs587777862
• NM_004408.4:c.1076G>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_004408.4(DNM1):​c.1076G>C​(p.Gly359Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G359R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNM1 NM_004408.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 10.0
• Publications: 14 publications found

Genes affected

DNM1 (HGNC:2972): (dynamin 1) This gene encodes a member of the dynamin subfamily of GTP-binding proteins. The encoded protein possesses unique mechanochemical properties used to tubulate and sever membranes, and is involved in clathrin-mediated endocytosis and other vesicular trafficking processes. Actin and other cytoskeletal proteins act as binding partners for the encoded protein, which can also self-assemble leading to stimulation of GTPase activity. More than sixty highly conserved copies of the 3' region of this gene are found elsewhere in the genome, particularly on chromosomes Y and 15. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

DNM1 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 31A

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• developmental and epileptic encephalopathy, 31B

  Inheritance: AR, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_004408.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-128222543-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 520737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 9-128222544-G-C is Pathogenic according to our data. Variant chr9-128222544-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 156559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM1	NM_004408.4	c.1076G>C	p.Gly359Ala	missense_variant	Exon 8 of 22	ENST00000372923.8	NP_004399.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM1	ENST00000372923.8	c.1076G>C	p.Gly359Ala	missense_variant	Exon 8 of 22	1	NM_004408.4	ENSP00000362014.4
DNM1	ENST00000634267.2	c.1076G>C	p.Gly359Ala	missense_variant	Exon 8 of 22	5		ENSP00000489096.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 31A Pathogenic:3

Feb 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 359 of the DNM1 protein (p.Gly359Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of DNM1-related conditions (PMID: 25262651). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 156559). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DNM1 protein function with a positive predictive value of 80%. This variant disrupts the p.Gly359 amino acid residue in DNM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28667181; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Feb 05, 2022

DASA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1076G>C;p.(Gly359Ala) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 156559; OMIM: 602377.0003; PMID: 25262651) - PS4_supporting. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 27066543) - PS3_supporting. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Dynamin) - PM1. This variant is not present in population databases (rs587777862; gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 520737 - c.1075G>A;p.(Gly359Arg)) - PM5. The variant was assumed de novo; but without confirmation of paternity and maternity (PMID: 25262651) - PM6. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic.

Oct 02, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.;.;.;T;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;.;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.7	H;H;H;H;.;H;.;H;.
PhyloP100		10
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.6	D;D;D;D;.;D;.;.;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;D;D;D;.;D;.;.;.
Sift4G	Uncertain	0.0070	D;D;D;D;D;D;D;D;D
Vest4		0.83
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.97
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587777862; hg19: chr9-130984823;